Cytotoxic chemotherapy agents have a steep dose response relationship and a narrow therapeutic index. The majority of cytotoxic chemotherapy doses are individualised for each patient and most commonly calculated based on the patient’s body surface area (BSA), renal function or weight. BSA has been shown to correlate with cardiac output, total blood volume as well as renal function. Various formulae exist to estimate BSA using height and weight with the Mosteller and Dubois formula’s being those most commonly used. For medications that are cleared through glomerular filtration such as carboplatin, area under the curve (AUC) dosing is used because there is a strong correlation between carboplatin clearance and creatinine clearance.
Doses of biological therapies including monoclonal antibodies and oral targeted therapies may be calculated using the BSA or patient weight. Fixed dosing, where the same dose is used regardless of patient parameters, is more commonly used with oral targeted therapy.
There is no evidence to support the use of one formula for calculating BSA over another. The Mosteller formula is the easiest to remember and calculate and therefore may be more widely used in clinical practice. It also provides an accurate estimation of BSA in underweight, normal weight and overweight/obese patients and is applicable to children.
Although it is common practice that dose adjustments are made if the patient’s weight varies by greater than 10% during treatment, there is no evidence that this should be undertaken.
Consensus recommendations suggest that overweight/obese patients with curable diseases can be under-dosed if the BSA is capped to prevent toxicities. Dosing according to the actual body weight of the patient may achieve better outcomes with documented safe toxicity profiles. Although these recommendations were made for patients with solid tumour malignancy it is reasonable to extrapolate this in the haematology malignancy setting.
Consensus guidelines are available to inform dosing of cytotoxic chemotherapy used in conditioning regimens for autologous or allogeneic transplant in the setting of obese overweight patients.
Fixed or flat dosing
Fixed dose or flat dose prescribing does not take into account body size or organ function and is rarely used for cytotoxic chemotherapy. The 2012 American Society of Clinical Oncology (ASCO) expert panel recommends consideration of fixed dosing for a few select cytotoxic agents in the context of specified protocols and tumour types (e.g. vincristine, bleomycin and carboplatin). On the basis primarily of neurotoxicity concerns, vincristine is capped at a maximum dose of 2 mg when used as part of the CHOP [cyclophosphamide, doxorubicin, vincristine, prednisolone and CVP (cyclophosphamide, vincristine, prednisone)] regimens.
Glomerular filtration rate (GFR) dosing
In the majority of circumstances dose calculations for carboplatin are based solely on renal function. Generally, glomerular filtration rate (GFR) is estimated using serum creatinine and calculated according to the Cockcroft-Gault equation. Other methods used to estimate the GFR include the Modification of Diet in Renal Disease (MDRD) study equation and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The latter is more widely reported automatically by clinical laboratories every time a creatinine is measured. Although the MDRD and CKD-EPI equations have been shown to be more accurate, the majority of recommendations for dose adjustments in renal impairment were made based on the assumption that the GFR was estimated using the Cockcroft-Gault equation. This formula is usually applied to calculate creatinine clearance (CrCl) prior to dosing.
Limited studies have been done in the obese population with regards to estimates of CrCl using the Cockcroft-Gault equation. Excess fat often causes a reduction in daily creatinine urine excretion per kg of body weight, and can sometimes overestimate CrCl.
Doses of cytotoxic chemotherapy should be dosed according to the actual body weight and/or BSA of the patient where there is a curative intent, unless a protocol specifies otherwise. Obesity alone should not be used as a rationale for capping BSA for chemotherapy dosing (Hunter et al, 2009; Griggs et al, 2012; Field et al, 2008).
Methods for calculating BSA should be standardised and the same method used by all clinicians at the institution. Many electronic programs (e.g. an oncology information system or computerised prescribing systems) allow the auto-calculation of BSA using the height and weight and for CrCl using the Cockcroft-Gault equation. Most available systems have configurable calculators embedded, thereby allowing each institution to select which formula they wish to use.
Special consideration should be given to calculating doses for individuals with poor performance status or those with co-morbidities which may affect tolerability and drug clearance. Dose capping or dose reductions made in this setting should be based on the individual patient parameters and clinical evidence (Gurney, 2002; Gurney, 2006). All doses that deviate from a standard evidence-based protocol should be clearly documented.
Specialised autologous or allogeneic transplant settings should adopt specific dosing policies related to the conditioning regimens used. Consensus guidelines are available (Bubalo et al, 2014).
Renal function should be used when calculating doses for renally excreted chemotherapy such as carboplatin. The Cockcroft Gault formula is the most accepted estimation of CrCl for chemotherapy dosing. In obesity, actual body weight should be used in the calculation of CrCl via the Cockcroft-Gault method to obtain more reliable measures of renal function. The original Cockcroft-Gault formula to estimate GFR used actual body weight, as no patients were obese. Therefore by using actual body weight for obese patients in the Cockcroft-Gault calculation, it can result in an overestimate of the GFR and a higher than needed carboplatin dose.
The re-weighing of the patient during therapy to recalculate the BSA and subsequent doses will depend on local policy, treatment intent and the extent of weight change. Dose adjustment should be made according to the presence or absence of toxicity, as well as changes in other factors that may affect medication elimination such as renal and hepatic function and concomitant medication. All dose reductions that deviate from a standard evidence-based protocol should be clearly documented. The checking of the patient's renal function during therapy with carboplatin to recalculate the carboplatin doses will depend on local policy, treatment intent and the extent of renal function change.
The calculation for BSA should be standardised and the same method used by all clinicians at the institution. The use of printed tables and slide-rules for the calculation of BSA is an out-dated practice and should be avoided.
For carboplatin, if an estimated GFR based upon measured serum creatinine is used in the Calvert formula, consideration should be given to limit the maximal GFR for the calculation to 125 mL/min (U.S. Food and Drug Administration, 2015). This recommendation does not apply if the GFR is directly measured.
Limited studies have been performed in the obese cancer population with regards to estimates of CrCl using the Cockcroft-Gault equation. As the Cockcroft-Gault formula overpredicts CrCl in obesity, lean or ideal body weight may be used to correct for excess fat. In obesity, ideal body weight should be considered in the calculation of CrCl when using the Cockcroft-Gault method to obtain more reliable measures of renal function.
Direct measurements of GFR using radiolabelled EDTA must be considered for patients receiving adjuvant or higher dose carboplatin.
Calculated doses may require ‘rounding’ to enable delivery of a measurable dose for both parenteral and oral doses and will depend on local practice (e.g. doxorubicin 53.85 mg could be rounded to 54 mg).
Dose adjustments should be made according to the presence or absence of toxicity, as well as changes in other factors that may affect medication elimination such as renal and hepatic function and concomitant medication. Dose adjustments are less commonly required with monoclonal antibodies.
Weight-based dosing is only used for a few cytotoxic chemotherapy agents including cladribine, melphalan and arsenic. This is largely based on how medicines were initially developed.
In the absence of data suggesting increased toxicity for underweight or obese individuals receiving weight-based dosing, doses should be based upon actual body weight.
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